Increased postoperative complications after laparoscopic gastrectomy in patients with preserved ratio impaired spirometry.

BACKGROUND: Preserved ratio impaired spirometry (PRISm), defined as decreased forced expiratory volume in the first second in the setting of normal ratio, is associated with an increased risk of respiratory disease and systemic comorbidities. Unlike severe obstructive pulmonary disease, little is known about the impact of PRISm on short-term outcomes in patients undergoing laparoscopic gastrectomy (LG) and its association with small airway dysfunction (SAD). METHODS: This study enrolled 830 patients who underwent preoperative spirometry and LG between January 2021 and August 2023. Of these, 228 patients were excluded. Participants were categorized into 3 groups based on their baseline lung function, and postoperative outcomes were subsequently analyzed. Potential associations between postoperative outcomes and various clinical variables were examined using univariate and multivariate analyses. RESULTS: PRISm was identified in 16.6% of the patients, whereas SAD was present in 20.4%. The incidence of postoperative pulmonary complications (PPCs) was notably higher in the SAD group (20.3% vs 9.8%, P = .002) and the PRISm group (28.0% vs 9.8%, P < .001) than the normal group. Among the 3 groups, pneumonia was the most frequently observed PPC. Multivariate analysis revealed that both SAD (odds ratio [OR], 2.34; 95% CI, 1.30-4.22; P = .005) and PRISm (OR, 3.26; 95% CI, 1.80-5.90; P < .001) independently constituted significant risk factors associated with the occurrence of PPCs. Univariate analysis showed that female was a possible risk factor for PPCs in PRISm group. CONCLUSION: Our study showed that PRISm and SAD were associated with the increased PPCs in patients undergoing LG for gastric cancer.

High immunocompetence in chronic hepatitis patients with normal alanine transaminase levels and and negative hepatitis B e-antigen for the progression of liver fibrosis.

INTRODUCTION: This study aimed to investigate the role of immunocompetence in chronic hepatitis B (CHB) patients with normal alanine transaminase (ALT) levels and negative hepatitis B e antigen (HBeAg) in the risk assessments of the progression of liver fibrosis. METHODS: We collected the clinical data of 57 patients with CHB, with normal ALT levels and negative HBeAg from December 2020 to December 2022. With hepatitis B virus (HBV) DNA > 20 IU/mL and ALT ≤ 40 U/L, these patients had never undergone antiviral therapy. The levels of CD4+ , CD4+ CD25+ , CD8+ , and CD4+ CD25+ CD127LOW regulatory T cells (Tregs) in the patients were detected using flow cytometry; the liver stiffness measurement (LSM) values of the patients were detected using Fibroscan. RESULTS: There was a statistically significant difference between the levels of fibrosis-4 (FIB-4) and hepatitis B surface antigen (HBsAg) when the cutoff point was HBsAg ≥ 1500 (p < .001). FIB-4 was negatively correlated with HBsAg (R = -0.291, p = .028) and positively correlated with age (R = 0.787, p < .001). LSM was negatively correlated with Treg but this correlation was not statistically significant (p > .05). Findings based on the analysis using logistic regression were as follows: (i) age was the independent risk factor when FIB-4 was used as the indicator for assessing liver fibrosis; (ii) Treg was the independent risk factor when LSM was used as the indicator for assessing liver fibrosis. When Treg was used to predict liver fibrosis, the cutoff value, diagnostic efficacy, area under the receiver operating characteristic (ROC) curve, and p value of the ROC curve were 6.875, 0.641, 0.84, and .027, respectively. CONCLUSION: Age and Treg are independent risk factors for progressive liver fibrosis. The cutoff value of Treg > 6.81 indicates the need for timely antiviral treatment and can serve as an indicator for evaluating liver fibrosis.

A New HEK293 Cell with CR2 Region of E1A Gene Deletion Prevents the Emergence of Replication-Competent Adenovirus.

PURPOSE: To eliminate the contaminants of Replication-Competent Adenovirus (RCA) during high titer recombinant oncolytic adenovirus production. METHODS: At first, we detected E1A copy numbers of different sources of 293 cells using Q-PCR, and we screened a subclone JH293-C21 of the JH293 cell line (purchased from ATCC) with lower early region 1A (E1A) copy numbers and higher adenovirus production ability. Then, we deleted the conserved region (CR)2 of the E1A gene in this subclone using the CRISPR-Cas9 system and obtained a stable cell clone JH293-C21-C14 with lower E1A expression, but the RCA formation had no significant reduction. Then, we further deleted the CR2 of JH293-C21-C14 cells with the CRISPR-Cas9 system and obtained a strain of cells named JH293-C21-C14-C28. Finally, we detected the capacity for cell proliferation, adenovirus production, and RCA formation in the production of recombinant adenovirus. RESULTS: The JH293-C21-C14-C28 cells had a similar cell proliferation ability and human adenovirus production as JH293-C21 cells. Most importantly, RCA production in JH293-C21-C14-C28 cells was lower than in JH293-C21 cells. CONCLUSION: Human adenovirus producer cell clone JH293-C21-C14-C28 with CR2 deletion can effectively prevent the RCA production of replication-competent oncolytic adenovirus; this will provide significant advantages in utility and safety in gene therapy.

Grounded theory-based analysis of occupational health and safety management modes in supply chain by core enterprises --evidence from China.

The implementation of occupational health and safety management in the supply chain by core enterprises is a significant step towards improving the working conditions of their suppliers. To guide core enterprises to adopt active and effective management modes, it is crucial to identify the characteristics of different management modes and classify them accordingly. This paper employs the grounded theory method to conduct an in-depth analysis of occupational health and safety management modes within the supply chain of core enterprises. This research mainly adopts semi-structured interview method. A total of 16 person-times are interviewed, and 210,000 words of in-depth interview scripts are obtained. After three coding process of the grounded theory，the evolution model of occupational health and safety management modes in supply chain by core enterprises was established. The research results indicate that core enterprises currently employ three modes of occupational health and safety management for their suppliers: defensive mode, passive mode, and strategic mode. Different modes have distinct characteristics in four dimensions of cognition, motivation, strategy and result. This research may provide strategic guidelines for core enterprises to evolve from the defensive mode to the strategic mode.

Stepwise formation of a chemodynamic therapy agent of {Cu8} macrocyclic complex recognized by iodide ions.

An atomically precise Cu(I) macrocyclic complex Cu8I was developed for chemodynamic therapy (CDT) research. The {Cu8} macrocyclic skeleton gradually forms with the selective recognition of iodide ions, and the monitoring of intermediate fragments during Cu8I formation using time-dependent electrospray ionization mass spectrometry indicates the following possible formation process: [Cu1] → [Cu2] → [Cu3] → [Cu4] → [Cu5I] → [Cu6I] → [Cu7I] → [Cu8I] when recognized by iodide ions. Furthermore, the Cu(I)-mediated Fenton-like reaction in Cu8I catalyzes the production of toxic ˙OH from H2O2, which results in efficient tumor suppression.

A Cu(I)-based Fenton-like agent inducing mitochondrial damage for photo-assisted enhanced chemodynamic therapy.

Increasing the reactive oxygen species (ROS) content at the tumor site is one of the effective strategies to promote intracellular oxidative stress and improve therapeutic efficiency. Herein, an atomically precise cinnamaldehyde-derived metal-organic Cu(I) complex (denoted as DC-OD-Cu) was rationally constructed. DC-OD-Cu could preferentially accumulate in the mitochondria of HeLa cells due to the mitochondria-targeting ability of triphenylphosphine, which was accompanied by the generation of large amounts of highly toxic hydroxyl radicals (˙OH) via Cu(I)-mediated Fenton-like reactions. Meanwhile, greater ROS generation jointly results in mitochondrial damage under white LED light irradiation. Furthermore, the in vitro and in vivo results suggested that DC-OD-Cu possesses favorable cytotoxicity and inhibits tumor growth. We believe that this research might provide a controllable strategy to construct multifunctional metal organic complexes for ROS-involved CDT.

Molecular Epidemiology of Community-Acquired Methicillin-Resistant Staphylococcus aureus and Clinical Characteristics of Different Sites of Infection.

Purpose: Since community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) was recognized, the molecular epidemiology of CA-MRSA in China has been diverse. It is unclear whether different sites of CA-MRSA infection differ in antimicrobial resistance and clinical characteristics. The purpose of this study was to identify the molecular types, virulence factors and antimicrobial resistance of CA-MRSA strains and to analyze the clinical characteristics of different sites of CA-MRSA infection. Methods: 26 CA-MRSA strains were screened from Beijing Chao-Yang Hospital from 2014 to 2022. SCCmec type, MLST type, spa type, Panton-Valentine leukocidin (PVL), hemolysin α (Hla), phenolic soluble regulatory protein α (PSMα), toxic shock syndrome toxin-1 (TSST-1), and enterotoxin (SE) A to E were detected by PCR and gene sequencing. Antimicrobial susceptibility tests and the clinical features of CA-MRSA infection cases were collected for statistical analysis. Results: The predominant type of CA-MRSA was ST59-t437-IV. New non-epidemic types, SCCmec VII, were also found. PVL was seen in 65.4% of CA-MRSA strains and TSST-1 was only be detected in 3.8% of CA-MRSA strain which caused poor prognosis. There were three types of infections: pneumonia (61.5%), infective endocarditis (7.7%), and skin and soft tissue infections (SSTIs) (30.8%). CA-MRSA pneumonia cases were secondary to influenza infection (37.5%). Patients with CA-MRSA-associated infective endocarditis were more likely to have underlying cardiac diseases. Patients with CA-MRSA-associated SSTIs were more likely to have a history of diabetes mellitus, and strains in this group were more susceptible to erythromycin and clindamycin. Conclusion: ST59-t437-IV was the primary CA-MRSA type in our research and in China. We proposed that TSST-1 might be one of the indicators to predict the severity and prognosis of CA-MRSA infection. Different sites of CA-MRSA infection had difference in antibiotics susceptibility testing and underlying diseases of patients. It could provide a new perspective on treating different types of CA-MRSA infection.

A triphenylphosphine coordinated Cu(I) Fenton-like agent with ferrocene moieties for enhanced chemodynamic therapy.

A triphenylphosphine coordinated Cu(I) complex of Fc-OD-Cu was rationally designed for chemodynamic therapy (CDT) of cancer. The complex was capable of generating a highly toxic hydroxyl radical (˙OH) via a Fenton-like reaction induced by Cu(I) moieties and simultaneously mediated by ferrocene moieties. As a result, the CDT efficiency of Fc-OD-Cu is higher than that of Ba-OD-Cu (without ferrocene moieties) and Fc-OD (without Cu(I) moieties).

Land Premium Effects of Urban Rail Transit and the Associated Policy Insights for TOD: A Case of Ningbo, China.

With considerable investments, mainly from local government budgets, the construction and operation of urban rail transit (URT) can exert significant spillover effects on the surrounding land use and land prices. In particular, China's local governments are actively committed to developing their URT systems and promoting large-scale transit-oriented development (TOD) projects under the public land leasing policy. However, the connection between the land premium effects and TOD policy and practice is still lacking, particularly in the local government contexts, which exhibit significant policy and spatial heterogeneity. Thus, this research represents an attempt to better address this issue using the city of Ningbo as a case study. First, the premium effects of URT on land prices are examined, after which three crucial policy insights (land value capture [LVC], public-private cooperation [PPC], and urban regeneration) are proposed to enhance the effectiveness and efficiency of TOD, demonstrating its strong connection with the potential premium effects. The findings demonstrate that (1) local governments have adopted different innovative policies-with the ambition-to implement LVC; (2) assisted by PPC, the local rail transit authority can significantly amplify the premium effects, although it must still address the fair distribution of premiums across multiple stakeholders; and (3) transit-oriented urban regeneration can significantly influence land prices/land rents and subsequently generate significant gentrification, which will be further addressed by the TOD policy and practice.

Ultra-processed foods and allergic symptoms among children and adults in the United States: A population-based analysis of NHANES 2005-2006.

Design: There is a strong correlation between dietary intake and allergic diseases. Ultra-processed foods (UPFs) are gradually becoming dominant worldwide and causing health problems for children and adults. We hope to determine whether links exist between UPFs and allergic symptoms. Methods: We investigated data from 2,736 children (16-19 years) and 4,256 adults (≥20 years) from the National Health and Nutritional Examination Survey (NHANES) 2005-2006. The associations between the mean UPFs contribution to total energy intake and all allergic symptoms (IgE, current asthma, allergy, rash, sneeze, wheeze, eczema, and hay fever) were estimated by weighted multivariate logistic regression. Results: Logistic regression analysis showed UFPs were negatively associated with IgE levels in children. Those with higher quartiles had a reduced risk from 16% (OR, 0.84, 95%CI, 0.55 to 1.28) to 34% (OR, 0.66, 95%CI, 0.49 to 0.89), p for trend = 0.006. UPFs were also positively related to current asthma in children with an increased risk of 11% (OR, 1.11, 95%CI, 0.79 to 1.56) to 76% (OR, 1.76, 95%CI, 1.10 to 2.82), p for trend = 0.0393. UPFs were also associated with eczema in girls. But there was no association observed between UPFs and allergic symptoms in adults. Conclusion: Our results suggested that UPFs assessed by the NOVA system were associated with IgE, current asthma in children, and eczema in girls. These results further support the need to test the association of modern dietary patterns with allergic symptoms.

Role of Built Environments on Physical Activity and Health Promotion: A Review and Policy Insights.

As urbanization and motorization continue worldwide, various health issues have emerged as a burden between individuals, families and governments at all levels. Under the prevalence of chronic disease, this review synthesizes research on the impact of the various built environments on the multiple health outcomes from a methodological and mechanistic perspective. Besides, it attempts to provide useful planning and policy implications to promote physical activity and health benefits. The finds show that: (1) Current literature has used a variety of dataset, methods, and models to examine the built environment-health benefit connections from the perspective of physical activity; (2) The prevalence of chronic diseases is inextricably linked to the built environment, and policy interventions related to physical activity and physical and mental wellbeing of urban residents should be emphasized; (3) The impact of the built environment on health is manifested in the way various elements of the physical environment guide the lifestyle of residents, thereby influencing physical activity and travel; (4) Given the changes that have occurred in the built environment during the current urban expansion, the link between urban planning and the public health sector should be strengthened in the future, and the relevant authorities should actively pursue policies that promote urban public health in order to improve the health of residents. Finally, it proposes potential policy insights for urban planning and development toward a healthier city and society.

A triphenylphosphine coordinated cinnamaldehyde-derived copper(I) Fenton-like agent with mitochondrial aggregation damage for chemodynamic therapy.

Chemodynamic therapy (CDT), which uses agents to induce cell death by decomposing endogenous hydrogen peroxide (H2O2) into highly toxic hydroxyl radicals (˙OH), has been recognized as a promising approach to treat cancer. However, improving the efficiency of ˙OH production is considered one of the biggest challenges that limits the therapeutic efficacy of CDT. Herein, to controllably and efficiently induce oxidative damage through the production of ˙OH, we developed a new metal complex CDT agent with atomically precise structural characteristics as a deviation from traditional nanomaterial-CDT agents. The obtained CDT agent, a cinnamaldehyde derived copper(I) complex (denoted Cin-OD-Cu), was found to be continuously enriched in the mitochondria of A2780 ovarian carcinoma cells, which was accompanied by the generation of large amounts of ˙OH via Cu(I)-mediated Fenton-like reactions of H2O2, thereby stimulating oxidative stress in the mitochondria and eventually leading to cell death. Moreover, in vivo experiments showed that Cin-OD-Cu was capable of effectively inhibiting tumor growth with excellent biocompatibility. We believe this research enriches the limited selection of atomically precise metal complex CDT agents in particular for reactive oxygen species-mediated treatments aimed at inducing mitochondria oxidative damage; we anticipate that it will provide new insights into the development of novel, atomically precise agents for CDT.

Safety of inactivated SARS-CoV-2 vaccines in patients with allergic diseases.

BACKGROUND: Considering the considerable prevalence of allergic disease in the general population, an urgent need exists for inactivated SARS-CoV-2 vaccines that can be safely administered to those subjects. METHODS: This retrospective cohort study including 1926 participants who received inactivated SARS-CoV-2 vaccines, compared their local and systemic reactions in 7 days after each dose of inactivated SARS-CoV-2 vaccine, and anti-SARS-CoV-2 IgG after vaccination in all participants. RESULTS: Pain at the injection site within seven days after the first injection was the most commonly reported local reaction, occurring in 31.0% of the patients with allergic disease and 18.9% in the control group, respectively (P < 0.001). After the first dose, systemic events were more frequently reported in patients with allergic disease than control group (30.2% vs. 22.9%, P < 0.001). After the second dose, systemic events occurred less often, affecting 17.1% of the patients with allergic disease and 11.1% of the control group (P < 0.002). The occurrence of fatigue, vertigo, diarrhea, skin rash, sore throat were the most frequent systemic reactions. Overall, a lower incidence of local and systemic reactive events was observed after the second dose than the first dose in patients with allergic disease and control group. Nearly all participants had positive IgG antibodies, and participants with allergic disease had higher frequencies compared with control group (100.0 vs.99.4%). CONCLUSIONS: Although local and systemic reactions were more frequently reported in patients with allergic disease than control group, administration of the inactivated SARS-CoV-2 vaccine was safe and well tolerated by all participants; no participants experienced a serious adverse event, and none were hospitalized. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2100048549. Registered Jul 10, 2021.

The evaluation index system of non-rigid demand service quality in safety production: based on the whole process.

The evaluation index system of non-rigid demand service quality in safety production delineates the production safety-related services that are procured by enterprises from service organizations and are not mandatory by the state. Construction of the evaluation index system of non-rigid demand service quality in safety production is an effective way to improve the quality of the demand service. Based on the INDSERV model and on-site interviews, this study constructs a whole-process safety production non-rigid demand service quality evaluation model, clarifies the evaluation indicators and conducts on-site investigations to verify the effectiveness of the model, and further analyzes the data to determine each evaluation index weight. A safety production non-rigid demand service quality evaluation index and evaluation scale were constructed. Effective exploration was performed on the evaluation index system of non-rigid demand service quality in safety production, which provides a guarantee for promoting the development of the non-rigid demand service market.

Independent risk factors of asthma exacerbations: 3-year follow-up in a single-center prospective cohort study.

Background: Because minimizing future risk is the goal of asthma chronic asthma management, it is particularly important to identify risk factors. We conducted this 3-year single-center prospective cohort study to determine the independent risk factors of asthma exacerbations (AEs). Methods: We performed this prospective, longitudinal, observational study with a 3-year follow-up on 257 patients aged 18-81 years with at least a 1-year history of asthma. Follow-up visits are conducted through regular annual phone calls, and the primary endpoints were AE. Results: The uncontrolled group was more likely to develop AE than the well-controlled group [odds ratio (OR): 6.34, 95% confidence interval (CI): 1.14-35.21, P<0.05]. Patients with low Asthma Quality of Life Questionnaire (AQLQ) scores were more likely to develop AE than these with high AQLQ scores (OR: 0.59, 95% CI: 0.35-0.99, P<0.05). AQLQ and Asthma Control Questionnaires (ACQ) were both strong independent risk factors within 3 years of enrollment; the cut-off values (COV) of the AQLQ and the ACQ (uncontrolled) that better evaluated the risk with the AE were ≤5.4 and >1, respectively. The AQLQ scores had a sensitivity of 79.07% and a specificity of 59.09% [area under curve (AUC): 0.70, P<0.0001], and the ACQ (uncontrolled) had a sensitivity of 81.4% and a specificity of 52.29% (AUC 0.68, P<0.0001). Conclusions: The findings of this study suggest that patients with uncontrolled asthma and a diminished health-related quality of life had an increased risk of exacerbations in the future. Defining these risk factors associated with AE is important as it will identify these at the highest risk to patients and may guide future interventions.

Synthetic MUC1 breast cancer vaccine containing a Toll-like receptor 7 agonist exerts antitumor effects.

Adjuvant immunotherapy has recently emerged as a potential treatment strategy for breast cancer. The tumor-associated protein mucin 1 (MUC1) has received increasing attention due to its high expression in numerous types of common tumors, in which MUC1 acts as a cancer antigen. However, the simple mixed composition of an adjuvant and a peptide is not a sufficient rationale for a MUC1 peptide-based vaccine. The present study developed a novel Toll-like receptor 7 (TLR7) agonist-conjugated MUC1 peptide vaccine (T7-MUC1), which elicited an effective immune response and a robust antitumor effect in a mouse breast cancer model. In vitro, T7-MUC1 significantly increased the release of cytokines in mouse bone marrow dendritic cells and spleen lymphocytes, and induced the dendritic cell-cytokine-induced killer response against tumor cells with high MUC1 expression. In vivo, it was observed that the 4T1 tumor weights in mice immunized with the T7-MUC1 conjugate were reduced by ≥70% compared with those in the control group. Furthermore, the therapeutic responses in vivo were attributed to the increase in specific humoral and cellular immunity, including high antibody titers, antibody-dependent cell-mediated cytotoxicity and cytotoxic T-lymphocyte activity. The percentages of CD3+/CD8+ T-cells were significantly higher in the T7-MUC1 treatment group compared with those in the control group. Therefore, the results of the present study suggested that the T7-MUC1 vaccine inhibited tumor growth in mice and thus may have potential as a therapeutic candidate in clinical trials for breast cancer immunotherapy.

Gastric cancer vaccines synthesized using a TLR7 agonist and their synergistic antitumor effects with 5-fluorouracil.

BACKGROUND: Vaccines play increasingly important roles in cancer treatment due to their advantages of effective targeting and few side effects. Our laboratory has attempted to construct vaccines by conjugating TLR7 agonists with tumor-associated antigens. Furthermore, immunochemotherapy has recently become an appealing approach to cancer therapy. 5-fluorouracil (5-FU), a commonly used chemotherapeutic agent, can reportedly potently and selectively kill tumor-associated MDSCs in vivo. METHODS: Gastric cancer vaccines were synthesized by the covalent attachment of our TLR7 agonist with the gastric cancer antigen MG7-Ag tetra-epitope, leading to T7 - ML (linear tetra-epitope) and T7 - MB (branched tetra-epitope). Cytokines induced by the vaccines in vitro were assessed by ELISA. A tumor challenge model was created by treating BALB/c mice on either a prophylactic or therapeutic vaccination schedule. 5-FU was simultaneously applied to mice in the combination treatment group. CTL and ADCC activities were determined by the LDH method, while CD3+/CD8+, CD3+/CD4+ T cells and MDSCs were evaluated by flow cytometry. RESULTS: In vitro, rapid TNF-α and IL-12 inductions occurred in BMDCs treated with the vaccines. In vivo, among all the vaccines tested, T7 - MB most effectively reduced EAC tumor burdens and induced CTLs, antibodies and ADCC activity in BALB/c mice. Immunization with T7 - MB in combination with 5-FU chemotherapy reduced tumor sizes and extended long-term survival rates, mainly by improving T cell responses, including CTLs, CD3+/CD8+ and CD3+/CD4+ T cells. 5-FU also enhanced the T7 - MB efficiency by reversing immunosuppressive factors, i.e., MDSCs, which could not be validly inhibited by the vaccines alone. In addition, T7 - MB repressed tumor growth and immune tolerance when the therapeutic schedule was used, although the effects were weaker than those achieved with either T7 - MB alone or in combination with 5-FU on the prophylactic schedule. CONCLUSIONS: A novel effective gastric cancer vaccine was constructed, and the importance of branched multiple antigen peptides and chemical conjugation to vaccine design were confirmed. The synergistic effects and mechanisms of T7 - MB and 5-FU were also established, observing mainly T cell activation and MDSC inhibition.

Identification of two regulatory genes involved in carbomycin biosynthesis in Streptomyces thermotolerans.

Carbomycins are 16-membered macrolide antibiotics produced by Streptomyces thermotolerans ATCC 11416T. To characterize gene cluster responsible for carbomycin biosynthesis, the draft genome sequences for strain ATCC 11416T were obtained, from which the partial carbomycin biosynthetic gene cluster was identified. This gene cluster was approximately 40 kb in length, and encoding 30 ORFs. Two putative transcriptional regulatory genes, acyB2 and cbmR, were inactivated by insertion of the apramycin resistance gene, and the resulting mutants were unable to produce carbomycin, thus confirming the involvement of two regulatory genes in carbomycin biosynthesis. Overexpression of acyB2 greatly improved the yield of carbomycin; however, overexpression of cbmR blocked carbomycin production. The qPCR analysis of the carbomycin biosynthetic genes in various mutants indicated that most genes were highly expressed in acyB2-overexpressing strains, but few expressed in cbmR-overexpressing strains. Furthermore, acyB2 co-expression with 4″-isovaleryltransferase gene (ist), resulted in efficient biotransformation of spiramycin into bitespiramycin in S. lividans TK24, whereas ist gene regulated by acyB2 and cbmR would cause the lower efficiency of spiramycin biotransformation. These results indicated that AcyB2 was a pathway-specific positive regulator of carbomycin biosynthesis. However, CbmR played a dual role in the carbomycin biosynthesis by acting as a positive regulator, and as a repressor at cbmR high expression levels.

Immunomodulatory and Antitumor Effects of a Novel TLR7 Agonist Combined with Lapatinib.

As new treatment approaches, both immunotherapy and targeted treatments have been used in the clinical treatment of cancers. These therapies are different from traditional surgery, chemotherapy and radiotherapy. Use of a combination of immunotherapy and targeted treatments may improve tumor clearance. We investigated the feasibility of combining tyrosine kinase inhibitors (TKIs, targeted drugs) and SZU-101 (a novel TLR7 agonist synthesized by our laboratory). Thirteen different TKIs were combined with or without SZU-101 and studied to determine their effects on immunocytes. On the basis of the distinctive results, lapatinib and sunitinib were selected for further tumor-inhibition investigation and determination of the underlying mechanism. Interestingly, we found lapatinib to work better with SZU-101, enhancing tumor clearance in vivo, without affecting the TLR7-NF-κB pathway activated by the TLR7 agonist in mouse spleen lymphocytes and bone marrow dendritic cells (BMDCs).

New C-19-modified geldanamycin derivatives: synthesis, antitumor activities, and physical properties study.

Thiazinogeldanamycin (2) was identified from Streptomyces hygroscopicus 17997 at the late stage of the fermentation. The pH was firstly proposed as an important factor in the biosynthesis of it. It was verified that 2 was produced by direct chemical reactions between geldanamycin (1, GDM) and cysteine or aminoethanethiol hydrochloride at pH > 7 in vitro. The proposed synthesis pathway for compound 2 was also discussed. Eleven new C-19-modified GDM derivatives, including five stable hydroquinone form derivatives, were synthesized, most of which exhibited desirable properties such as lower cytotoxicity, increased water solubility, and potent antitumor activity. Especially, compounds 5 and 8 showed antitumor activities against HepG2 cell with IC50 values of 2.97-6.61 µM, lower cytotoxicity and at least 15-fold higher water solubility compared with 1 in pH 7.0 phosphate buffer.